Application of Lithiation–Borylation to the Total Synthesis of (−)-Rakicidin F

The stereochemistry of the lipophilic side chain of (+)-rakicidin F had not been determined until recently. Using our lithiation–borylation methodology (“assembly line synthesis”) we were able to efficiently prepare the all-syn isomer as well as the C-21 epimer of the side chain, and comparison with the natural product suggested that the natural product had all-syn stereochemistry. Completion of the total synthesis using a macrolactamization of the northern amide enabled us to confirm Wang and Chen’s stereochemical findings for the structure of (+)-rakicidin F.


Glassware, Solvents and Reagents
All manipulations were performed with oven-dried (130 °C for a minimum of 12 h) or flame-dried glassware using standard Schlenk techniques under an atmosphere of nitrogen, unless otherwise stated.
All anhydrous solvents were commercially supplied or dried using an Anhydrous Engineering alumina column drying system (THF,toluene,Et2O,CH2Cl2). Reagents were purchased from commercial sources and used as received. All organolithium reagents were titrated against N-benzylbenzamide. [1]

Chromatography and Instrumentation
Thin layer chromatography (TLC) was performed using Merck Kieselgel 60 F254 fluorescent treated silica adsorbed onto aluminium, components were visualized under UV light, or by staining with aqueous basic potassium permanganate followed by heating, p-anisaldehyde solution followed by heating, Hanessian's stain (CAM stain) followed by heating, or an ethanolic solution of phosphomolybdic acid followed by heating, as stated.
Flash column chromatography (FCC) was carried out using Sigma-Aldrich silica gel (60 Å, 230-400 mesh, 40-63 μm) or a Biotage Isolera TM flash purification system. In cases where automated column chromatography was employed, the solvent gradient and flow rate are indicated.
NMR spectra were recorded at various field strengths, as indicated, using Bruker 400 MHz, Varian VNMR 400 MHz, Varian VNMR 500 MHz, or Bruker Cryo 500 MHz for 1 H, and 13 C acquisitions. All NMR spectra were recorded at 25 °C unless otherwise stated. Chemical shifts (δ) are reported in parts per million (ppm) and IR spectra were recorded neat as a thin film on a Perkin Elmer Spectrum One FT-IR. Selected absorption maxima (νmax) are reported in wavenumbers (cm −1 ).

Naming of Compounds
Compound names are generated by ChemDraw Professional 20.0 software (PerkinElmer), following the IUPAC nomenclature.

N 2 -(tert-butoxycarbonyl)-N 5 -(2,4-dimethoxybenzyl)-L-glutamine (32)
In a 250 mL round bottom flask, SI-4 (5.31 g, 10.9 mmol, 1.0 equiv) was dissolved in dry EtOH (100 mL). After the addition of Pd/C 10% (581 mg, 0.55 mmol, 5 mol%), the reaction vessel was subjected to three cycles of evacuation followed by venting with N2. Then, the reaction vessel was subjected to three cycles of evacuation followed by venting with H2 (balloon). The black suspension was stirred under an H2 atmosphere for 18 h. After this time, the reaction mixture was filtered through a Celite pad (2 cm) and the residue was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure to give crude 32 (4.64, 91% purity by 1 H-NMR, 10.7 mmol, 98%) as a white foam and was used without further purification for step 2.4.1.
In a flame-dried Schlenk flask, stannane 25 [3] (2.82 g, 6.42 mmol, 1.3 equiv) was dissolved in dry Et2O (26 mL) and cooled to -78 °C. At this temperature n-BuLi (1.61 M in hexanes, 3.99 mL, 6.42 mmol, 1.3 equiv) was added dropwise over 40 min (0.1 mL/min) to the colorless solution. After completion of the addition, the resulting yellow solution was stirred at -78 °C for 80 min. Then, a solution of 24 (2.22 g, 4.94 mmol, 1.0 equiv) in dry Et2O (10 mL) was added dropwise (0.1 mL/min). The resulting pale-yellow solution was stirred at -78 °C for 3.5 h and then allowed to warm to rt. After further 12.5 h (overnight), the reaction mixture was filtered through a pad of silica [~40 mm depth of wetted (Et2O) silica, using a filter frit connected directly to a round bottom flask] to give a pale-yellow solution. The silica was washed with Et2O (80 mL). The filtrate was concentrated under reduced pressure to give 3.18 g of a pale-yellow oil. The crude mixture was used directly for step 2.3.6.

-3-(dimethyl(phenyl)silyl)-2,4,6,8-tetramethyldecyl)oxy)triethylsilane (SI-9)
In a 50 mL round bottom flask, olefin 29 (222 mg, 0.481 mmol, 1.0 equiv) was dissolved in dry EtOAc (10 mL) after which PtO2 (10.9 mg, 0.048 mmol, 10 mol%) was added. The reaction vessel was then subjected to three cycles of evacuation followed by venting with N2. Then, the reaction vessel was subjected to three cycles of evacuation followed by venting with H2 (balloon). The black suspension was subsequently stirred under a H2 atmosphere (balloon) for 20 h, before the mixture was filtered through a Celite pad (2 cm). The residue was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure to give crude SI-9 (385 mg) as a pale-yellow oil. The crude mixture was used directly for step 2.3.12.